The US Food and Drug Administration's committee of independent vaccine experts gathered Thursday to discuss the future of COVID-19 shots. The meeting seemed primed for explosive debate. Earlier in the week, the FDA released documents that made clear the agency is holding steadfast to its idea that COVID vaccines will fit the mold of annual flu shots—with reformulations decided in the first half of each year, followed by fall rollouts in anticipation of winter waves.
But outside experts, including some on the FDA's advisory committee, have questioned almost every aspect of that plan—from the uncertain seasonality of COVID-19 so far, to the futility of chasing fast-moving variants (or subvariants, as the case may be). Some have even questioned whether there's a need to boost the young and healthy so frequently when current vaccines offer protection against severe disease, but only short-lived protection against infection.
One particularly outspoken member of FDA's committee, Paul Offit, a pediatrician and infectious disease expert at Children’s Hospital of Philadelphia, has publicly assailed the bivalent booster, writing a commentary piece in the New England Journal of Medicine earlier this month titled: Bivalent Covid-19 Vaccines — A Cautionary Tale. (The FDA's advisory committee voted 19-2 in support of the bivalent boosters last year, with Offit being one of the two votes against.)
Yet, despite the charged background of yesterday's meeting, the sparks of disagreement fizzled over a calm discussion. The nine-hour meeting culminated with a unanimous vote by the committee in favor of "harmonizing" future formulations of COVID-19 vaccines so that primary series and boosters are matched formulations. For example, the primary series vaccines would match the updated bivalent boosters, which currently target both the original strain of SARS-CoV-2 that came out of Wuhan, China, as well as omicron subvariants BA.4/5.
Streamlining
The FDA seemed to soften the ground with questions and discussion topics focused on "harmonizing" and simplifying COVID vaccines. After the single vote, the agency directed the committee to discuss "simplifying the immunization schedule," before getting to the more perilous, but still gentle discussion topic of considering "periodic updates to COVID-19 vaccine composition."
Overall, the committee members favored streamlining vaccines where possible—making primary series shots match booster doses, and potentially whittling down regimens to one dose for adults and two for children and high-risk adults.
"There's so much confusion about these different formulations that I think anything we can do to ease up on that confusion and simplify things, it's going to be a good thing," said Archana Chatterjee, Dean of Chicago Medical School and a voting committee member, said at the end of yesterday's meeting. "I concur with my other colleagues that there definitely remains a need for these vaccines and for us to do our best to get them into arms. Having vaccines is not sufficient, we need to have them be used. ... This is a step in the right direction in getting us there."
But, the bigger steps for future vaccines—deciding what formulation should be used next, who should get them, and when—remained elephant-sized questions in the meeting room. And even among the relatively placid comments, it was clear that large disputes were bubbling under the surface.
Before the committee's vote and discussion, the advisors listened to a series of presentations from vaccine makers, the FDA, and the Centers for Disease Control and Prevention, which all provided updates on the state of COVID-19 and the performance of the vaccines so far.
Data dive
Although Offit and others have criticized the bivalent boosters for not being better than the previous boosters, the data presented in the meeting argued otherwise. Real-world observational data shows an advantage for people boosted with the bivalent booster compared with the original (monovalent) vaccine—even against the more recent subvariants. Data presented during the meeting shows it has outcompeted the original vaccine in terms of protection against symptomatic infection, visits to the emergency department or urgent care visits, and hospitalization.
In a CDC study published Wednesday, for instance, researchers found that the bivalent booster's relative vaccine effectiveness against symptomatic infection with a BA.5-related omicron sublineage (which includes BQ.1 and BQ.1.1) was 52 percent among people from 18 to 49 years old. In other words, people in this age group had 52 percent more protection against infection with BA.5-related strains than people who received the original booster. For ages 50 to 64, the relative effectiveness against BA.5-related infection was 43 percent, and it was 37 percent among those 65 years and older.
Against the more recent XBB/XBB.1.5-related omicron subvariants, relative effectiveness against infection was 49 percent among people 18 to 49, 40 percent among people 50 to 64 years, and 43 percent among those 65 years and older.
There's also been a slew of serology studies looking at how the bivalent booster's antibody responses compare with those from the original booster when up against the gamut of currently circulating omicron subvariants. The results are mixed and, in some cases, hard to compare due to differences in intervals between vaccination, the number of people involved, and the types of assays used. But overall, the FDA argued that they suggest that the bivalent booster provides better neutralizing antibody responses against currently and recently circulating omicron subvariants than the original vaccine.
"The important thing is that the results all trend in the same direction," Jerry Weir, director of the FDA's Division of Viral Products, said in the meeting Thursday. "In other words, with all of these studies just like those from the manufacturers, there is improved variant-specific neutralization following administration of the bivalent BA.4/5 vaccine compared with the monovalent… I find it somewhat remarkable to see that level of uniformity."
For instance, one of the most recently published studies, released Wednesday in the New England Journal of Medicine, found that a bivalent boost led to a roughly threefold increase in neutralizing antibody levels against XBB.1 compared with people boosted with the original booster. That increase was roughly the same (3.6-fold and 2.7-fold) among people without and with previous SARS-CoV-2 infection, respectively.
Despite criticism by Offit and others before the meeting, committee members seemed comfortable with the bivalent data, accepting the FDA's rosy retrospective.
"I'm totally convinced that the bivalent vaccine is beneficial as a primary series and its boosters," committee member David Kim, an infectious disease expert at the Department of Health and Human Services, said.
Variant selection
But, the question of whether future vaccines will be similarly bivalent seemed contentious. Some wondered if the part of the vaccine targeting the Wuhan strain—which is no longer circulating—is helping. The reason it was included last year was that initial data suggested having it provides broader protection, which would be valuable if a new variant emerges that is more like the original strain than the current omicron lineage. But some members seemed to now doubt such a scenario is likely.
Stanley Perlman, an infectious disease expert at the University of Iowa who acted as the committee chair yesterday, drew a comparison to another circulating human coronavirus, 229E. That virus, which is associated with mild illnesses, has evolved over time so that antibodies from 30 years ago no longer neutralize the circulating strains, he remarked. "This is relevant, I think, because one of the things about keeping the ancestral strain in the [COVID] vaccine is the question of whether we would go back to that original variant," Perlman said. "With 229E, it doesn't seem to have happened," he noted and wondered aloud if SARS-CoV-2 would be similar. "Maybe we're never going to end up going back there, so maybe it's not important."
Others briefly touched on the concern of imprinting, a phenomenon in which the immune system's responses are biased toward fighting the version of a pathogen it first encounters, potentially making subsequent responses to different versions less effective. Researchers are still studying this phenomenon with respect to SARS-CoV-2 responses. But there's widespread concern for the possibility that repeated boosting with Wuhan-targeting vaccines could end up hampering responses to newer variants.
"One of the biggest questions that we're going to have to think about—and I know this will be discussed in later discussions, but—is do we include the primary strain, the Wuhan strain, in future vaccines," Steven Pergam, an infectious disease expert at Fred Hutchinson Cancer Center, said amid the discussion. "I think that's a real big question we're going to have to debate."
But, if not the Wuhan strain, what strain or strains should be included? Many committee members noted the futility of chasing variants. The FDA seemed to agree but argued that the goal of discussing (potentially annual) reformulations would be to continue to improve the vaccines.
"The object of course—before anyone says anything— is not to chase variants. None of us think that's realistic," the FDA's Weir said. "But I think our experience so far with the bivalent vaccines that we have do indicate that we can continue to make improvements to the vaccine and that would be the goal of these meetings."
Flu model
The frequency of those meetings to reassess vaccine formulation was also a fraught question. The FDA, of course, argued for at least annual meetings—sometime in May or early June, so that vaccine formulations could be decided with enough time for vaccine manufactures to have updated doses for the fall, ahead of winter waves. But committee members pushed back, noting that the winter waves were not necessarily established. There's simply not enough data yet. And although there have been winter waves, there have also been summer waves.
Peter Marks, the FDA's top vaccine regulator, chimed in to defend the flu-like reformulation model. While acknowledging that the seasonality of COVID-19 is not yet established, he raised an argument he and other FDA officials made in an editorial last year, that is, that winter is the best time to vaccinate for COVID-19 because it coincides with peaks in other respiratory viruses, such as influenza and RSV.
"When do we have to worry about the worst overwhelming of the hospitals? It will be when we have influenza, RSV, and potentially COVID at the same time," Marks said. Another advantage is that if people can get a flu shot and a COVID shot simultaneously, it could increase uptake. "Overall, this seems like a reasonable way to go."
"I just want to echo something," he added later in the discussion. "We totally agree with everyone: This isn't flu." But, on the other hand, he argued, the flu model has served us well. "So we can take the best of that model and essentially adjust around it."
Committee members seemed wary of committing to an annual schedule, though a plan for a fall reformulation seemed reasonable for at least the coming year.
"We're not going to know how often to do it," committee member Eric Rubin, an infectious disease expert and editor-in-chief of the New England Journal of Medicine, said. "I think it's quite reasonable to think about another one for the fall. … For step one, that would be ok. It's hard to say that it's going to be annual at this point."
Dose of data
Apart from the formulations, the committee also left lingering questions about dosage and doses. The committee indicated it would prefer to simplify the current regimens, particularly for young children in the age range of 3 to 5 years, who currently have available either a two-dose or a three-dose series.
For young children, Moderna's two-dose vaccine appeared 47 percent effective after one dose and 57 percent effective after two. For Pfizer-BioNTech's three-dose vaccine, data suggests it was just 12 percent effective after one dose (though the confidence interval stretched below zero for this, suggesting it could offer lower or no protection). Protection jumped to 39 percent after two, but there was no clear data for assessing the efficacy of the third dose. It will clearly take more data with different doses to determine if a two-dose series is possible with Pfizer's vaccine.
In the end, the committee called for a plethora of data to match the many unanswered questions. "I think there's a general agreement that updating the vaccine composition is good," Perlman said in a final summary. "And that whether it comes to being once a year or how it actually pans out, that we need to have as much information as we can."
Annual? Bivalent? For all? Future of COVID shots murky after FDA deliberations - Ars Technica
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